After radiation the PSA slowly
declines. The low point or nadir may not be reached for several
years. Rather than continuously declining, occasionally the PSA may
temporarily rise which is referred to as a PSA bounce. PSA bounce is
a common phenomenon after prostate brachytherapy and occurs at a
rate of 17–31%, depending on the definition used. It is more common
in younger patients, those receiving higher implant doses, and those
with larger glands. PSA bounce does not predict for future PSA
failure.

To calculate the actuarial risk of
developing a prostate-specific antigen (PSA) bounce after prostate
brachytherapy alone, using three definitions of bounce mentioned in
the literature, and to explore the relationship between disease and
treatment variables and the risk of developing a bounce. The impact
of PSA bounce on PSA failure was also explored.

Prostate-specific antigen (PSA) is a
sensitive measure of treatment outcome after radiotherapy (RT) for
prostate cancer. Unlike after radical prostatectomy, when PSA should
be undetectable after treatment, the PSA level after RT falls slowly
and may intermittently increase over a number of years. This may be
due to PSA release from partially damaged normal prostatic
epithelium and/or the long time it may take for lethally damaged
cancer cells to die and stop producing PSA. This is especially
relevant for prostate brachytherapy, in which it takes 2–10 months
for the seeds to deliver their entire radiation dose. Because of the
nature of PSA decline after RT, the American Society for Therapeutic
Radiology and Oncology (ASTRO) created guidelines for biochemical
failure that used three consecutive elevations of PSA to signal
failure. Elevations in PSA that occur months to years after
treatment and that subsequently fall can confound this definition
and make it difficult to distinguish an actual failure from what has
been described as a benign PSA bounce.

Various definitions of PSA bounce
have been used. Critz defined a PSA bounce as a rise of 0.1 ng/mL
after brachytherapy and external beam RT (EBRT). Cavanagh
described a temporary increase ≥0.2 ng/mL. Pruthi believed
that a PSA bounce should be defined as a rise in PSA of >35% from
the baseline prior value. This opinion was based on the work of
Prestigiacomo and Stamey who noted that overall PSA
variability was 35% in patients without prostate cancer. This
variability was composed of physiologic and assay variation. Hanlon
defined a PSA bounce after EBRT as a rise of 0.4 ng/mL during a
6-month period. The level and significance of a bounce may also be
different depending on the type of RT delivered.

The current study examined PSA bounce
after brachytherapy alone without hormonal therapy or EBRT. The
incidence of PSA bounce was calculated using three different
definitions (≥0.1 ng/mL, ≥0.4 ng/mL, and >35%). In addition, the
effects of pretreatment disease and treatment-related factors on PSA
bounce were analyzed to determine which patients were at increased
risk of developing a bounce. Finally, the relationship of PSA bounce
to biochemical failure was explored.

Methods and materials

A total of 373 patients with T1–T2
prostate cancer underwent radioactive seed implant using 125I (n =
337) or 103Pd (n = 36) without hormonal therapy or external beam RT.
All patients had a minimum of 1 year (median 4, maximum 11) of
follow-up and at least three follow-up PSA values. PSA bounce was
defined by a rise of one or two PSA values with a subsequent fall.
Three definitions of bounce were used: definition 1, rise ≥0.1 ng/mL;
definition 2, rise ≥0.4 ng/mL; and definition 3, rise >35% of
previous value.

Results

The
actuarial likelihood of
experiencing a PSA bounce at 5 years was 31% for definition 1, 17%
for definition 2, and 20% for definition 3. The median time to
develop a bounce was 19.5 months for definitions 1 and 2 and 20.5
months for definition 3. Gleason score, initial PSA level,
and clinical stage did not predict for bounce using any definition.
Using definition 1, younger patients (≤65 years) had a bounce rate
at 5 years of 38% vs. 24% for older patients (p = 0.009). 125I
patients receiving an implant dose of ≤160 Gy had a bounce rate
(definition 1) at 5 years of 24% vs. 38% for those receiving a dose
delivered to 90% of the gland on the 1 month postimplant dose–volume
histogram (D90) >160 Gy (p = 0.04). Using definition 2, prostate
volume significantly affected the incidence of bounce. Patients with
larger glands (>35 cm3) were more likely to experience a bounce (23%
at 5 years) than those with smaller glands (≤35 cm3) who had a
bounce rate of 11% at 5 years (p = 0.01). In a multivariate analysis
of factors predicting for PSA failure, PSA bounce was not found to
be significant.

Discussion

The recognition of PSA bounce is
important in treating patients who receive RT for prostate cancer.
Unlike radical
prostatectomy, with which the PSA level should fall to undetectable
levels, RT, and especially brachytherapy, cause a gradual decline in
PSA. PSA values may take as long as 4–5 years to reach a nadir.
During this time, fluctuations in PSA levels may cause great anxiety
for patients. The intact prostate, with its normal and abnormal
epithelial cells, is the source for these PSA fluctuations. A
transient rise in PSA has been recognized since PSA began to be used
as a tool to monitor disease progress. This PSA bounce was mentioned
in the original ASTRO consensus statement that provided guidelines
for monitoring PSA levels after RT and was one of the reasons that
three consecutive PSA rises were used to define failure.

Various definitions of PSA bounce
have been cited in the literature. In the current report, three
reported definitions (rise of ≥0.1, ≥0.4, and >35% of baseline) were
used to calculate the actuarial bounce rate after brachytherapy. A
comparison of these rates demonstrated that definition 1 would lead
to a higher bounce rate (31%) than definition 2 (17%) or 3 (20%) at
5 years. The rate of 31% is
similar to the 35% rate reported by Critz after implant and
EBRT using the same definition. In addition, Cavanagh also
noted a PSA bounce (≥0.2 ng/mL)
in 35.8% of patients treated with brachytherapy with or
without EBRT. Definition 2 led to a lower actuarial bounce rate of
17% at 5 years compared with the bounce rate after EBRT reported by
Hanlon of 31%. Of note, all the above-mentioned studies used crude
rates to estimate the risk of bounce, and the current study used
actuarial methods, which more accurately estimate the risk of
developing a bounce over time. The definition proposed by Pruthi
(>35%) led to a bounce rate of 20%, similar to the rate calculated
using definition 2. Because patients become concerned with any rise
in their PSA level, all definitions are equally valid, unless one is
associated with a greater likelihood of developing PSA failure.

In the current series, PSA
bounce (using all three definitions) did not predict for PSA
failure. In a multivariate analysis of potential predictors
of PSA failure, bounce was not found to be a significant predictor.
This is similar to the findings reported by Critz. Of note, using
definition 1, PSA bounce predicted for PSA control. An explanation
for this is that patients with a PSA bounce (definition 1) were more
likely to have received a higher dose implant, and higher dose
implants are associated with lower PSA failure rates. This
explanation is supported by the multivariate analysis of PSA
failure, which revealed dose, but not bounce, to be a significant
predictor. This contrasts
with the findings of Hanlon who found that patients developing
a bounce had a significantly lower biochemical disease-free rate
(47%) compared with those who did not (66%). This suggests that the
bounce phenomenon may be different after EBRT than after
brachytherapy.

The ability of prognostic variables
to predict for a bounce varied depending on the definition used.
Calculations with definition 1 revealed that both younger age (<65
years) and greater implant dose (>160 Gy for 125I) were associated
with an increased incidence of bounce (38% at 5 years). The effect
seen with age may be secondary to increased testosterone levels,
although this was not measured in the current study, or more
reactive epithelial cells. The increased rate of bounce seen with
higher doses may be related to a greater likelihood of a
radiation-induced inflammatory reaction. This contrasts with the
findings of Hanlon that showed that patients with a bounce were
treated to lower median dose than those without a bounce. This again
suggests that PSA bounce after EBRT may be different and have
different implications than the bounce seen after brachytherapy.

The cause of this PSA bounce is
unknown, but the timing of its occurrence suggests that it may be
related to a late radiation reaction. The
median time to bounce ranged
from 19.5 to 20.5 months using all three definitions. This time to
bounce is similar to the time to develop radiation proctitis and
erectile dysfunction A similar finding was reported in the
study by Critz in which the median time to bounce
was 18 months after implant.
These findings differ from those of Hanlon, who noted a median time
to bounce of 35 months.
It is also important to note that a bounce occurred as late as 88
months after implant. Unlike the report from Critz, in which the PSA
bounce was not seen in patients treated with combined implant and
EBRT after 5 years, patients treated with implant alone can
experience a transient rise in PSA as long as 9 years after
treatment.

PSA bounce is a common
phenomenon after brachytherapy and occurs at a rate of 17–31%,
depending on the definition used. The similar findings of the
current report to those found by Critz suggest that the
mechanism for this bounce is the same whether the patient receives
an implant alone or in combination with EBRT. On the other hand, it
appears that PSA bounce after brachytherapy may be different from
that seen after EBRT. The lower rate of bounce, earlier time to
bounce, differing effect of dose, and lack of effect on PSA failure
compared with the phenomena seen after EBRT suggest that they may be
two different types of PSA profiles. The data after EBRT suggest
that PSA bounce may represent an early manifestation of PSA failure
in a certain percentage of patients and the phenomena seen after
brachytherapy seem to have little effect on PSA failure developing.
All this information can help aid physicians in providing counsel to
patients during their postbrachytherapy follow-up period.

Conclusion

PSA bounce is a common phenomenon
after prostate brachytherapy and occurs at a rate of 17–31%,
depending on the definition used. It is more common in younger
patients, those receiving higher implant doses, and those with
larger glands. PSA bounce does not predict for future PSA failure.

Using the magnitude of PSAbounce after MRI-guided
prostate brachytherapy to distinguish recurrence, benign
precipitating factors, and idiopathic
bounce

To identify events that precipitated
a prostate-specific antigen (PSA) bounce and characterize the
magnitude, duration, and time to PSA bounce after MRI-guided
prostate brachytherapy. Between 1997 and 2001, 186 patients with
low-risk prostate cancer underwent MRI-guided permanent 125I source
implantation, with or without external beam radiotherapy. A PSA
bounce was defined as a ≥15% elevation in PSA compared with the most
recent value, followed by a decline to a level at or less than the
prebounce value. At the time of PSA measurement, data were
prospectively collected on whether the patient had recent
ejaculation, ongoing radiation proctitis, or recent instrumentation.

Brachytherapy has become a frequently
used treatment for early-stage prostate cancer. Although the
long-term outcome after brachytherapy for early-stage prostate
cancer remains to be determined, a recent study with up to 12 years
of follow-up reported excellent long-term disease control in a
cohort of patients treated with brachytherapy. Another study
demonstrated similar 5-year outcomes in low-risk prostate cancer
patients treated with brachytherapy compared with those treated with
radical prostatectomy or external beam radiotherapy (EBRT).

Serum prostate-specific antigen (PSA)
levels are used as a measure of disease recurrence after
brachytherapy, EBRT, and radical prostatectomy. After radical
prostatectomy, the PSA level declines to undetectable levels within
weeks. However, after RT, PSA remains detectable and falls more
slowly, because the prostate has not been removed. Hence, elevations
in PSA have been used as a marker for recurrence after RT. The
American Society for Therapeutic Radiology and Oncology (ASTRO)
Consensus Panel has defined biochemical failure as three consecutive
rises in PSA after RT for prostate cancer.

In addition to PSA elevations from
disease recurrence, prostate cancer patients treated with RT can
also show a temporary elevation in PSA without disease recurrence, a
phenomenon termed PSA bounce. PSA bounce has previously been defined
as an increase of ≥0.1 ng/mL followed by a subsequent decrease to
less than that level; as an increase of ≥0.2 ng/mL followed by a
decline; or as a minimal rise of 0.4 ng/mL during a 6-month period
followed by a drop of any magnitude.
PSA bounce is a very common
phenomenon in prostate cancer patients treated with brachytherapy or
EBRT. It has been reported in 24–36% of patients treated with
brachytherapy with or without EBRT and in 31% of patients
treated with EBRT alone. The etiology of PSA bounce remains
unclear. Bacterial and radiation prostatitis have been postulated as
possible mechanisms underlying PSA bounce. Previous studies have
also shown that transient elevations in PSA can arise from recent
ejaculation, instrumentation, and bicycle riding.

The PSA bounce phenomenon can
complicate the follow-up of prostate cancer patients treated with
brachytherapy. Clinicians may find it difficult to distinguish a PSA
bounce from disease recurrence, resulting in unnecessary biopsies or
salvage therapy. PSA bounce may also generate considerable anxiety
among patients. The purpose of this study was to characterize the
etiology, magnitude, and time course of PSA bounce to establish
whether the PSA kinetics after MRI-guided prostate brachytherapy can
differentiate between PSA bounce and disease recurrence.

: A total of 115 patients (61.8%) had
a total of 156 PSA bounces. Of these, 36 patients had PSA bounces
associated with ejaculation, proctitis, or instrumentation, and 79
experienced idiopathic PSA bounces (not associated with a
precipitating event). The magnitude of the PSA bounce was
significantly lower for the idiopathic PSA bounce (0.6 ng/mL)
compared with that associated with ejaculation (p = 0.003),
proctitis (p <0.0001), or instrumentation (p = 0.007). Patients with
biopsy-proven local recurrence had a median PSA elevation of 1.2 ng/mL,
significantly higher (p = 0.006) than the magnitude of the
idiopathic PSA bounce, but not significantly different from the
magnitude of the PSA bounce due to ejaculation, proctitis, or
instrumentation.

In patients treated with MRI-guided
prostate brachytherapy, recent ejaculation, instrumentation, or
ongoing radiation proctitis can cause a transient increase in PSA,
the magnitude of which is significantly higher than that for
idiopathic PSA bounce, but is similar to that in patients with
recurrent disease.

Patients with prostate cancer treated
with RT can experience a temporary elevation in serum PSA without
disease recurrence. This phenomenon, called a PSA bounce, occurs
commonly in prostate cancer patients treated with brachytherapy. A
PSA bounce can be difficult to distinguish from disease recurrence,
leading to a diagnostic dilemma for clinicians and anxiety among
patients.

No universally accepted definition
exists for PSA bounce. Previous studies have defined PSA bounce with
cutpoints of 0.1 ng/mL, 0.2 ng/mL, and 0.4 ng/mL. However, these
definitions may be confounded by the 15% assay variability in
commercially available assays for serum PSA. To avoid classifying
assay fluctuations as a PSA bounce, we defined PSA bounce as a ≥15%
elevation in serum PSA compared with the most recent value, followed
by a decline to a level at or less than the prebounce value. Even
with this more stringent definition, 61.8% of the patients
experienced one or more PSA bounces.

The incidence of PSA bounces in our
study was higher than the 24–36% rate reported in previous studies.
Multiple factors may have contributed to this difference. The
clinical characteristics of the patients, such as age, may have
differed from those in previous studies. The follow-up was twice as
frequent compared with a previous study and may have led to
the detection of a higher number of bounces. In our study, most of
the peripheral zone received a dose escalation to 150% of the
minimal peripheral dose and the transition zone received the minimal
peripheral dose or slightly less at the anterior base of the
prostate. This technique may have caused a higher incidence of
radiation proctitis, resulting in a higher frequency of PSA bounces.
The median time to the PSA
bounce was longer than the median time of 18–20.4 months reported in
previous studies, and this difference may also have been due
to variations in patient characteristics, treatment technique, and
follow-up.

The etiology for PSA bounce remains
unclear, although bacterial and radiation proctitis have been
postulated as possible mechanisms. In the present study, information
was prospectively collected about possible precipitating factors for
the PSA bounce. Recent
ejaculation, recent instrumentation, and ongoing radiation proctitis
accounted for 23% of the PSA bounces. Although previous
studies have shown that ejaculation and instrumentation can cause
transient elevations in PSA, ours is the first study to show that
ongoing radiation proctitis can cause a temporary PSA increase. Of
particular importance was the finding that the magnitude of PSA
bounce was significantly lower for idiopathic PSA bounces compared
with that associated with ejaculation, instrumentation, and
proctitis.

Distinguishing the PSA bounce from
disease recurrence presents a challenge to clinicians.
Ours is the first study to
indicate that the magnitude of PSA elevation may help distinguish a
PSA bounce from recurrence. Patients with an idiopathic PSA
bounce had a significantly lower median PSA elevation than did
patients with biopsy-proven local recurrence. In contrast, no
significant difference was found in the median PSA elevation in
patients with a PSA bounce associated with precipitating factors
compared with those with recurrence. Therefore, after ruling out
precipitating factors, the magnitude of the PSA elevation may help
distinguish an idiopathic PSA bounce from recurrence. However, the
overlap in the range of PSA elevations due to idiopathic bounce and
recurrence was considerable.
Although higher PSA elevations (>2.5 ng/mL) occurred only in
patients with recurrence and not in those with an idiopathic bounce,
lower PSA elevations occurred in both groups. The
present study was limited by the short median follow-up of 2.25
years. With longer follow-up, more patients may develop disease
recurrence, perhaps including some of the patients now thought to
have had a PSA bounce. Longer follow-up is necessary to characterize
this phenomenon of PSA bounce fully.

The study was also limited by the
small number of recurrences (n = 6), which makes it difficult to
draw firm conclusions about differences in PSA kinetics between an
idiopathic PSA bounce and disease recurrence. Despite the small
number of recurrences, the magnitude of PSA elevation was
significantly higher for patients with recurrence than for those
with idiopathic PSA bounces. Future studies with larger number of
recurrences can evaluate this difference in PSA elevation more
definitively. In addition, future studies are planned to evaluate
whether the prebounce PSA value or the PSA nadir can predict for
eventual biochemical recurrence.

Because PSA bounce commonly occurs in
prostate cancer patients treated with brachytherapy, clinicians
should make their patients aware of this phenomenon to forestall
anxiety. When a prostate cancer patient treated with brachytherapy
presents with an elevation in PSA, a detailed history should be
obtained to evaluate for precipitating factors. If precipitating
factors are ruled out, the magnitude of the PSA elevation may help
distinguish idiopathic PSA bounce from disease recurrence, thus
helping clinicians faced with this difficult diagnostic dilemma.